Novel insights into m6A modification of coding and non-coding RNAs in tumor biology: From molecular mechanisms to therapeutic significance

Abstract

Accumulating evidence has revealed that m⁶A modification, the predominant RNA modification in eukaryotes, adds a novel layer of regulation to the gene expression. Dynamic and reversible m⁶A modification implements sophisticated and crucial functions in RNA metabolism, including generation, splicing, stability, and translation in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Furthermore, m⁶A modification plays a determining role in producing various m⁶A-labeling RNA outcomes, thereby affecting several functional processes, including tumorigenesis and progression. Herein, we highlighted current advances in m⁶A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages. Meanwhile, we also focused on the therapeutic significance of m⁶A regulators in clinical cancer treatment.

Keywords: m6A; non-coding RNA; therapeutic target; tumor microenvironment.

Figure 1

Functions of m⁶A modification in mRNA. Writer proteins deposit m⁶A remarks in newborn mRNAs transcript from DNA.The m⁶A signal deposited in mRNA can adjust the local flanking sequences by the m⁶A flag installed in the mRNA and recruit YTHDC1, which manipulates mRNA alternative splicing and nuclear export. The mRNA labeling m⁶A can recruit IGF2BPs to stabilize the mRNA in the nucleus. After penetrating the cytoplasm, the m⁶A-labeled mRNA produces sophisticated and far-reaching biological effects. IGF2BP1/2/3 proteins recognize the m⁶A remark embedded in mRNA, influencing the mRNA stability. On the contrary, m⁶A deposited in mRNA can recruit YTHDF2/3, promoting target mRNA degradation. In addition, the presence of an m⁶A modified mRNA regulates target mRNA translation and, consequently protein synthesis. The binding of eIF3 and m⁶A pockets launches m⁷G-independent translation. The interplay between YTHDF2 and m⁶A sites existing in mRNA enhances translation elongation. YTHDF1/3 or YTHDC2 perceive m⁶A pockets, and promotes target mRNA translation initiation.

Figure 2

The roles of m⁶A modification in non-coding RNAs. METTL3 and hNRNPA2B1 promote pri-miRNA processing and mature miRNA output in the m⁶A tone. The m⁶A modification existing in long noncoding RNA influences its binding affinity with target miRNA, influencing the target mRNA of boundary miRNA (also called competitive endogenous RNA working mechanisms). YTHDC1 zooms lncRNA XIST -mediated gene silence. The m⁶A modification acts as a controlling element to regulate AS lncRNA functions. The m⁶A label in lncRNA also change the secondary structure via the m⁶A switch. The m⁶A signal existing in circRNA could be recognized as “self” circRNA, distinguishing itself from foreign circRNA and escaping RNA immunity. CircRNA launches cap-independent translation mediated by the YTHDF3/eIF4G2/eIF3A complex in an m⁶A dependent fashion.

Figure 3

Malfunctions of m⁶A regulators in various human cancers. Red regulators suggest an oncogenic character. In contrast, blue regulators suggest a tumor-suppressive character and the roles of green regulators are hard to define (controversial portrayal reported in the specific cancer type).

Figure 4

The interplay between m⁶A modification and the tumor microenvironment (TME). Several remarkable examples were reviewed below: (A) C1q⁺ TAM subpopulation-specific METTL14 deficiency induced tumor-infiltrating CD8⁺ T cell dysfunction by decreasing cytokine subunit Ebi3 mRNA stability, facilitating CD8⁺T cell exhaustion by increasing Tex cell and increasing Teff cell, and impeding CD8⁺T cells to eliminate tumors. (B) TGF-β inhibits METTL3 expression in tumor-infiltrating NK cells. By targeting SHP-2, METTL3 elevates the response of NK cells to IL-15 via the AKT-mTOR and MAPK-ERK signaling pathways, thus promoting the immunosurveillance of NK cells. (C) METTL3-deficiency in DC modulates co-stimulatory molecules (CD40 and CD80) and the translational efficiency of TLR signaling adaptor Tirap, which blocks T cell activation and responses by inhibiting cytokine IL-12 production mediated by TLR4/NF-κB signaling. (D) Hypoxia-induced GBM cell-specific ALKBH5 dramatically amplifies IL-8 production by eliminating m⁶A modification in lncRNA NEAT1, which triggers transcriptional suppressing factor SPFQ relocation from IL-8 promoter sequence to paraspeckles assembly mediated by NEAT1 stability.

Figure 5

Therapeutic implications of m⁶A regulators in cancer. Given the attractive prospect of targeting FTO and METTL3 in cancer treatment, numerous inhibitors of m⁶A modifiers have been developed.